Device to be implanted in a human or animal body for material or signal delivery or acquisition within the body, and method of implanting the device

ABSTRACT

For fixedly implanting a device for material or signal delivery or acquisition or a part of such a device in a human or animal body, an opening is provided in hard tissue of the body, the opening reaching through a hard tissue layer, e.g. through a cortical bone layer into cancellous bone underneath. The device includes a plug portion (P) and/or a cover portion (C) which includes a ring of a material having thermoplastic properties extending around the plug portion (P) or on a tissue facing surface of the cover portion (C). The opening provided in the hard tissue has a cross section at least in the area of its mouth that is adapted to the plug or cover portion such that the plug portion (P) can be introduced through the mouth of the opening or the cover portion (C) can be positioned over the mouth of the opening such that the ring extends around the opening, along its wall and/or on the hard tissue surface around its mouth.

CONTINUITY

This is a continuation-in-part of PCT/CH2010/000217, filed on Sep. 7,2010 and currently pending, which claims priority of U.S. application61/241,184, filed on Sep. 10, 2009.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is in the field of medical technology and relates to adevice of which at least a part is suitable for being implanted in ahuman or animal body and which is equipped for material or signaldelivery or acquisition within the body. The invention also concernsmethods for implanting the named implantable devices or implantabledevice parts.

2. Description of Related Art

Devices for material delivery within a body are in particular drugdelivery devices (delivering therapeutically or prophylactically activemolecules or particles into tissue) and infusion devices but may alsoserve for delivering other materials such as e.g. contrast agents orfluorescent molecules, viable cells (e.g. for differentiation andintegration in the tissue or for production of a desired protein) orsubatomic particles (particle radiation) within the body. Devices formaterial acquisition within a body are e.g. catheters or hollow needlesfor removing tissue components or body fluids e.g. for therapeutic ordiagnostic purposes. Devices for signal delivery within a body servee.g. for stimulating tissue, for activating deposited chemicals, or foractivating other implanted devices such as e.g. drug delivery devices,wherein the signals to be delivered within the body may be e.g.electric, mechanic, acoustic or optic signals. Devices for signalacquisition within a body serve e.g. diagnostic purposes, wherein thesignal acquisition may comprise e.g. acquisition of signals transmittedinto tissue, measuring a local body temperature, pressure, or chemistry,or sensing the state of another implanted device such as e.g. a drugdelivery device.

Devices for material or signal delivery or acquisition within a body mayalso be equipped for combinations of the above named functions such ase.g. a combination of signal delivery and signal acquisition fordiagnostic (e.g. scanning) purposes or a combination of a drug deliveryfunction combined with a signal acquisition function for detecting aneed for delivery in the concerned tissue and a signal delivery functionfor activation of the drug delivery function. In many cases the nameddevices comprise electronic or microelectric and/or micromechanicelements. The devices may be fully implanted or they may comprise partsto be implanted and parts which are situated outside of the body,wherein the implanted parts are physically or functionally connected orconnectable to the non-implanted parts, and wherein for such cases theinvention concerns the implanted device part only. Examples for suchonly partly implanted devices are e.g. devices comprising an implantedcatheter and non-implanted reservoir and drive means, devices comprisingan implanted sensor and a non-implanted device part for registration ofthe sensor readings, or systems comprising an implanted identificationchip (RFID) and a non implanted reading device.

The term “device for implantation in a human or animal body for materialor signal delivery or acquisition” as used in connection with thepresent invention is understood to comprise all the above named groupsand examples of implantable devices or implantable device parts and alldevices and device parts which one skilled in the art will subsume underthe named groups.

Implantable drug delivery devices are well known in today's medicine.Such drug delivery devices are usually designed for sustained and/ordelayed release of the drug, wherein the delivery process may becontrolled by chemical characteristics of the device (e.g. biologicalresorption of device components enclosing the drug), by control means,which are e.g. integrated in the device to activate the delivery eitherfully automatically or through signals or actions initiated from outsideof the body.

The known implantable drug delivery devices as well as other knownimplantable devices for material or signal delivery or acquisition suchas implantable devices comprising electronic or microelectric and/ormicromechanic elements (e.g. RFID-chips, sensors, cardiac pulsegenerators, electric or mechanic elements for activating deliverydevices) are implanted to be either “floating” (e.g. subcutaneouslyimplanted) or to be fixed in a specific body location (e.g. by beingtied to soft tissue with suture or wire or by being fixed to hard tissuewith the aid of a bone anchor with or without suture). Floatingimplantation is in particular known for RFID-chips (e.g. foridentification of animals) and for drug delivery devices. Fixedimplantation is more involved but in many cases advantageous as itprevents migration of the device in the body. Regarding drug delivery,fixed implantation is particularly advantageous if the drug is to beadministered locally, wherein the fixation location is chosen tocoincide as closely as possible with the location of the desiredadministration.

Drug delivery devices suitable for fixed implantation in bone tissue aree.g. described in the publication U.S. Pat. No. 6,936,270. The describeddevices comprise an e.g. metallic osteosynthesis element such as a bonescrew, bone nail or bone staple to be at least partly embedded in thebone tissue. The drug and possibly a suitable drug carrier is containedin the screw or nail head or in a container fixed to the middle sectionof the staple and the head or container is designed for delivery of thedrug to tissue or body fluid situated adjacent to the bone in which thedevice is anchored. The devices are said to be particularly suited forimplantation within a synovial joint and for delivering a drug into thesynovial fluid of the joint.

Also known (e.g. WO 2005/053795) are drug delivery devices in the formof cannulated bone screws comprising openings connecting the axial screwchannel with the threaded screw surface and containing the drug to bedelivered in the channel, the drug being delivered through the openingsto the bone tissue in which the screw is embedded.

Implantable drug delivery devices comprising an osteosynthesis element(e.g. bone screws or plates) being made of a biodegradable material aredescribed e.g. in the publication U.S. Pat. No. 6,214,008. According tothis publication, the drug (e.g. growth factor GF or bone morphogenicprotein BMP) is integrated in the biodegradable material of theosteosynthesis element and is released with a rate directly dependent onthe degradation rate of the biodegradable material. The devices are saidto be particularly advantageous for delivering the drugs to bone defectlocations, e.g. to a fractured bone tissue, for furthering bone repair.

For the above mentioned known drug delivery devices designed for fixedimplantation in bone tissue, the fixation of the device is usuallycoupled with producing a bone defect, i.e. an opening in the bone tissueoriginating from a bone surface (accessible bone surface) and usuallypenetrating a cortical bone layer to reach into the cancellous bonetissue situated beneath the cortical bone layer. This means that theopening, even if it is only small, constitutes a non-natural passagefrom a first body region (on the accessible side of e.g. the corticalbone layer) to a second body region (on the non-accessible side of e.g.the cortical bone layer), wherein characteristics, functions and needsof the two body regions may differ considerably, and wherein, before theopening was provided, the two body regions were naturally andappropriately sealingly separated from each other by e.g. the corticalbone layer. It is known that bone screws, bone nails or bone staplesimplanted in such openings are not capable of mending the naturalbarrier function of the cortical bone layer completely. Chemicals andeven bacteria will be able to pass through the impaired cortical bonelayer along the device surface, in particular when an initial press fithas relaxed or, in the case of bioresorbable devices, when resorptionhas started. This means that the above shortly described known drugdelivery devices, when fixed to or in bone not only constitute apossibly undesired impairment of a natural barrier function of thecortical bone layer but also are not able to fully limit delivery of thedrug to one side of the cortical bone layer, even if they are designedspecifically for such a purpose (delivery to accessible side of corticallayer according to U.S. Pat. No. 6,936,270 or delivery to non-accessibleside of cortical layer according to WO 2005/053795 or U.S. Pat. No.6,214,008).

BRIEF SUMMARY OF THE INVENTION

It is an object of the present invention to provide a further device formaterial or signal delivery or acquisition within a human or animalbody, the device or part thereof being suitable for fixed implantationin hard tissue of the human or animal body or in a correspondingreplacement material situated in the human or animal body. It is also anobject of the present invention to provide a method for implanting thedevice or part thereof. One particular improvement which can be achievedby using the device and method according to the invention concerns theirability to reconstitute the natural barrier function of a hard tissuelayer, in particular of a bone layer, which is to be penetrated onimplantation of the device or device part.

It is a further object of the present invention to provide a drugdelivery implant that is capable of ensuring an improved specificity ofthe body location and/or of the body tissue to which the drug isdelivered. It is yet another object of the present invention to providean implantation method for a drug delivery implant with improvedspecificity of the location and/or of the tissue to which the drug isdelivered. This means e.g. that the invention is to make it possible tofixate a drug delivery device in or on hard tissue, in particular bonetissue, wherein the fixation comprises penetration of a hard tissuelayer and wherein in spite of such penetration the drug delivery islimited to a much higher degree than possible according to the state ofthe art, to only one side of this hard tissue layer.

It is an even a further object of the present invention to provide asurgical method that includes implanting a drug delivery device for thepurpose of promoting tissue healing at a site where a soft tissue/softtissue replacement material is attached to hard tissue/hard tissuereplacement material.

These and other objects are achieved by the invention as defined in theclaims.

The invention is mainly based on the finding that liquefiedthermoplastic material brought into contact with hard tissue or acorresponding replacement material not only easily penetrates pores andopenings of the hard tissue or replacement material to constitute, onre-solidification, a positive fit connection therewith, but in additionis capable of contacting the hard tissue or replacement material in avery intimate manner such that on re-solidification the contact areaconstitutes a tight seal. In particular, it is found that the sealingcapability of the named contact area is far better and considerably lessprone to deterioration due to loading than the sealing capability of theabove named devices according to the state of the art, mainly bonescrews being screwed into a hard tissue opening or bone nails or staplesbeing impacted into the hard tissue.

According to an aspect of the invention, the implantable device formaterial or signal delivery or acquisition or the implantable part ofsuch a device comprises a plug portion and/or a cover portion and amaterial or signal delivery or acquisition portion wherein the plug orcover portion are attached or attachable to each other or fully separatefrom each other. The plug or cover portion comprises a material havingthermoplastic properties, which is situated around the plug portionand/or on the hard tissue facing side of the cover portion constitutingby itself a preferably complete ring or constituting at least part of aring arranged in a ring-shaped groove and protruding therefrom.

For implanting the device according to the aspect of the invention, anopening is provided in the hard tissue or replacement material, theopening reaching through a hard tissue layer from an accessible side toa non-accessible side thereof. A cross section of at least a mouthregion of the opening is adapted to the plug or cover portion of thedevice or device part. The device or device part is then positionedrelative to the hard tissue opening such that the ring of materialhaving thermoplastic properties or the groove containing such materialextends all around the opening, along the inside wall of the openingand/or along the hard tissue surface around the mouth of the opening.

At least part of the thermoplastic material is then liquefied and madeto get into contact with the inside wall of the opening or the hardtissue surface around the mouth of the opening (if applicable,simultaneously flowing along the groove to form a complete ring),advantageously combined with making the liquefied material to penetrateinto cavities or pores of the hard tissue. The liquefied material thenre-solidifies to constitute a sealing ring being anchored in the hardtissue or replacement material and extending all around the openingalong the inside wall of the opening (ring around plug portion) and/oralong the hard tissue surface around the mouth of the opening (ring oncover portion) and therewith to constitute a sealing connection orsealing ring between the liquefiable material and the hard tissue orreplacement material or preferably a combination of a sealing connectionand a positive fit connection therebetween.

Instead of implantation of the device or device part in a hard tissueopening, which is specifically made for such implantation, it ispossible also, to implant the device or device part in a hard tissueopening caused by other circumstances (e.g. bone fracture, removal ofbone tumor, pockets caused by periodontitis), wherein the implant ischosen to fit into the opening in the way as described above for aspecifically provided opening and wherein the sealing ring achievedduring the implantation may provide a sealing not only between thedevice or device part and bone tissue but possibly also between thedevice or device part and other tissue or other implant which may beimplanted beforehand or afterwards.

The in situ liquefaction of the material having thermoplastic propertiesis achieved by transmitting energy to the ring or part ring of materialhaving thermoplastic properties, preferably vibrational energy (inparticular ultrasonic vibration energy) being transmitted to thethermoplastic material possibly via other portions of the device ordevice part from e.g. a correspondingly shaped sonotrode of anultrasonic device. Therein the device or device part may be temporarilyattached to the sonotrode or the sonotrode may be pressed against aproximal face of the device or device part. However, it is possible alsoto achieve the desired liquefaction e.g. with the aid of laser lightbeing absorbed in the thermoplastic material to form the sealing ring orin a device area adjacent to this material or with the aid of resistiveor inductive heating of the thermoplastic material or an adjacent devicearea.

The sealing ring produced by implanting the device according to theaspect of the invention may be circular and extend in a substantiallyeven plane or it may have any other form (e.g. polygonal, oval,irregular and/or extending in a non-even plane). The material havingthermoplastic properties constituting the sealing ring may benon-bioresorbable or bioresorbable, wherein the character of theresorbability may need to be adapted to a desired delivery oracquisition characteristic and/or to expected tissue regeneration.Instead of being implanted through a hard tissue layer having a naturalsealing function as e.g. through a cortical bone layer, the deviceaccording to the invention may also be implanted in hard tissue withoutsuch a function, e.g. in cancellous bone tissue made accessible e.g. byother surgery, wherein in such a case the sealing function of thesealing ring is of a very minor importance.

The plug portion, the cover portion or a combination of plug and coverportion may constitute the whole implantable device or device part.Alternatively, the plug portion, cover portion or combination of the twomay carry further portions wherein these further portions may extendfrom the plug or cover portion distally or proximally and may beattached to the plug or cover portion before or after liquefaction andre-solidification of the liquefiable material comprised by the plug orcover portion. The ring or part ring of the material havingthermoplastic properties may constitute a body of this material which issuitably attached to further portions e.g. of non-liquefiable material(e.g. arranged in a groove of such other portions and protruding fromthe groove) or it may constitute a region of a non ring-shaped deviceportion, e.g. of a cylindrical or conical plug portion or of a plateshaped cover portion, which fully consist of the material havingthermoplastic properties.

One of many applications of above-discussed aspect of the invention issupport of tendon or ligament repair by local delivery of a bone growthfactor near the tendon/bone or ligament/bone interface. The bone growthfactor may be of the Bone Morphogenic Protein family (BMP 2, 6, 7, 12,13)/the transforming growth factor beta family, an Insulin Growth Factor(e.g. IGF 1), a Platelet Derived Growth Factor (PDGF), a Growth andDifferentiation Factor (e.g. GDF 5) etc. and also a combination thereofand/or other an other drug including a non-proteinaceous drug includingsmall molecules (e.g. biphosphonates), and/or anti-inflammatory and/orantibiotic drugs possibly in combination with a proteinaceous drug, etc.

In accordance with an other, second aspect of the invention, a surgicalmethod of fastening soft tissue and/or soft tissue replacement materialto hard tissue and/or hard tissue replacement material is provided, themethod comprising

fastening the soft tissue/soft tissue replacement material to the hardtissue/hard tissue replacement material using a fastener

implanting a device comprising surface regions of a material havingthermoplastic properties and being liquefiable through application ofenergy to the device, wherein the device is equipped for causing atleast part of the material having thermoplastic properties to liquefyand to bring the material into contact with the hard tissue/hard tissuereplacement material to form on re-solidification an anchor in the hardtissue/hard tissue replacement material, the device further comprising adrug promoting healing,

wherein the device is implanted near the interface between the softtissue/soft tissue replacement material and the hard tissue/hard tissuereplacement material.

“Near the interface” means at the interface or in a vicinity thereof.“At the interface” means, for example, that the further device isimplanted where the soft tissue is to be in physical contact with thehard tissue/replacement material. For example, the device may beimplanted so that a proximal surface is approximately flush with thehard tissue/replacement material surface and the soft tissue/replacementmaterial covers the device at least partially. “In a vicinity of theinterface” may mean that the device is not in physical contact with thesoft tissue but is close enough to ensure that the enhancedconcentration of released drug near the device causes adiagnosable/discernible enhancement effect on the tissue healing at theinterface.

If the device is a device according to the first aspect, the sealingring may be distal of a location at which the drug may be released tothe tissue so that the drug is released towards the tissue adjacent thecortical bone and prevented from getting into an interior of the bone.Alternatively, the sealing ring may be proximal of a location at whichthe drug may be released to the tissue so that the drug is releasedtowards the bone tissue and prevented from getting into the tissueadjacent the bone. As yet another alternative, drug releasing locationsmay be present on both sides of the sealing ring. As an even furtheralternative, the device may be different from a device according to thefirst aspect in that not a complete sealing ring is formed.

Embodiments that comprise releasing the substance towards the tissueadjacent the bone (the soft tissue) may be advantageous in that mutualengraftment of the hard and soft tissues (and/or replacement materials)is achieved, for example engraftment of bone and ligament/tendon tissue.Embodiments that comprise releasing the substance into the bone may beadvantageous in situations where the bone tissue has to heal and/or tobe strengthened.

In embodiments of the second aspect of the invention, the fastener or atleast one of a plurality of fasteners may be at least one of:

a fastener that comprises material liquefiable by the impact of energyand that is implanted by liquefying at least a portion of the material,pressing a liquefied portion of the material into the hardtissue/replacement material and letting the liquefied portionre-solidify to provide an anchoring. For example, this may be achievedby the method as described in any one of the publications: U.S. Pat. No.7,335,205, U.S. Pat. No. 7,008,226, US 2006/105295, US-2008/109080, andUS 2009/131947, incorporated herein by reference in their entirety.

A suture that is anchored by a suture anchor, wherein the suture anchorcomprises material liquefiable by the impact of energy and that isimplanted by liquefying at least a portion of the material, pressing aliquefied portion of the material into the hard tissue/replacementmaterial and letting the liquefied portion re-solidify to provide ananchoring. For example, this may be achieved by the method as describedin any one of the publications: U.S. Pat. No. 7,335,205, U.S. Pat. No.7,008,226, US 2006/105295, US-2008/109080, and US 2009/131947,incorporated herein by reference in their entirety.

A fastener (for example for ‘gluing’) such as an adhesive and/or anartificial tissue or absorbable material temporarily fastening the softtissue/soft tissue replacement material to the hard tissue/hard tissuereplacement material

In this, the suture may be secured to the suture anchor at any time,i.e. prior to the anchoring, during the anchoring, and/or thereafter.

In any embodiment that comprises using a suture anchor to fasten softtissue/replacement material to hard tissue/replacement material, thesuture anchor may be an anchor as described in U.S. 61/386,160,incorporated herein by reference in its entirety. It may be anchoredusing a device and/or a method as described in U.S. 61/386,160.Especially, it may be a suture anchor comprising a pin portion and amaterial having thermoplastic properties being arranged at least partlyaround a pin portion circumference, and, for locking the suture onimplantation, further comprising a suture groove extending in an axialdirection along the pin portion and having a zero depth portion at aproximal end of the pin portion, or a collapsible plurality of eyeletsat a distal end of the pin portion. Alternatively, it may be a sutureanchor as described in WO 2009/109057/U.S. patent application Ser. No.12/920,696 also incorporated herein by reference.

As already mentioned, it is preferred to liquefy the material havingthermoplastic properties by applying vibrational energy, in particularultrasonic vibration energy. This method corresponds with the per seknown implantation technique according to which an implant comprising amaterial having thermoplastic properties and being liquefiable bymechanical vibration is anchored in hard tissue, in particular in bonetissue, by applying such vibration to the implant, in particularultrasonic vibration. Such implantation techniques are disclosed e.g. inthe publications U.S. Pat. No. 7,335,205, U.S. Pat. No. 7,008,226, US2006/105295, US-2008/109080, and US 2009/131947. The whole disclosure ofall the named publications is enclosed herein by reference.

The basis of the above named implantation techniques is the in situliquefaction of a thermoplastic material having mechanical propertiessuitable for a mechanically satisfactory anchorage of the implant in thebone tissue, wherein the material in its liquefied state has a viscositywhich enables it to penetrate into natural or beforehand provided pores,cavities or other structures of the bone tissue, and wherein an onlyrelatively small amount of the material is liquefied such that anon-acceptable thermal load on the tissue is prevented. Whenre-solidified, the thermoplastic material which has penetrated into thepores, cavities or other structures constitutes a positive fitconnection with the bone tissue. Of course such positive fit connectioncan also be achieved in other suitably hard material of a suitablestructure or form such as e.g. porous bone replacement material orfurther implants, or simultaneously in both bone tissue and othermaterials situated adjacent to the bone tissue.

Suitable liquefaction combined with an acceptable thermal loading of thetissue and suitable mechanical properties of the positive fit connectionis achievable by using materials with thermoplastic properties having amodulus of elasticity of at least 0.5 GPa and a melting temperature ofup to about 350° C. and by providing such material e.g. on an implantsurface, which on implantation is pressed against the bone tissue,preferably by introducing the implant in a bone opening which isslightly smaller than the implant or by expanding the implant in a boneopening which originally is slightly larger than the implant (expansione.g. by mechanically compressing or buckling of the implant). Duringimplantation, the implant is subjected to vibration of a frequencypreferably in the range of between 2 and 200 kHz (preferably ultrasonicvibration) by applying e.g. the sonotrode of an ultrasonic device to theimplant. Due to the relatively high modulus of elasticity thethermoplastic material is able to transmit the ultrasonic vibration withsuch little damping that inner liquefaction and thus destabilization ofthe implant does not occur, i.e. liquefaction occurs only where theliquefiable material is in contact with the bone tissue and is therewitheasily controllable and can be kept to a minimum.

Instead of providing the liquefiable material on the surface of theimplant (disclosed e.g. in U.S. Pat. No. 7,335,205 or U.S. Pat. No.7,008,226), it is possible also to provide the liquefiable material in aperforated sheath and to liquefy it within the sheath and press itthrough the sheath perforations to the surface of the implant and intothe pores or cavities of the bone tissue (disclosed e.g. in U.S. Pat.No. 7,335,205 and U.S. Pat. No. 7,008,226) and/or it is possible toliquefy the liquefiable material between two implant parts of which oneis vibrated and the other one serves as counter element, the interfacebetween the two implant parts being positioned as near as possible tothe bone tissue (as disclosed in the publications US 2009/131947 andWO2009/109057).

Materials having thermoplastic properties suitable for the device andthe method according to the invention are thermoplastic polymers, e.g.:resorbable polymers such as polymers based on lactic and/or glycolicacid (PLA, PLLA, PGA, PLGA etc.) or polyhydroxy alkanoates (PHA),polycaprolactone (PCL), polysaccharides, polydioxanes (PD)polyanhydrides, polypeptides or corresponding copolymers or compositematerials containing the named polymers as a component; ornon-resorbable polymers such as polyolefines (e.g. polyethylene),polyacrylates, polymetacrylates, polycarbonates, polyamides, polyester,polyurethanes, polysulfones, polyarylketones, polyimides,polyphenylsulfides or liquid crystal polymers LCPs, polyacetales,halogenated polymers, in particular halogenated polyolefines,polyphenylensulfides, polysulfones, polyethers or equivalent copolymersor composite materials containing the named polymers as a component.

Specific embodiments of degradable materials are Polylactides like LR706PLDLLA 70/30, R208 PLDLA 50/50, L210S, and PLLA 100% L, all ofBöhringer. A list of suitable degradable polymer materials can also befound in: Erich Wintermantel und Suk-Woo Haa, “Medizinaltechnik mitbiokompatiblen Materialien und Verfahren”, 3. Auflage, Springer, Berlin2002 (in the following referred to as “Wintermantel”), page 200; forinformation on PGA and PLA see pages 202 ff., on PCL see page 207, onPHB/PHV copolymers page 206; on polydioxanone PDS page 209. Discussionof a further bioresorbable material can for example be found in CABailey et al., J Hand Surg [Br] 2006 April; 31(2):208-12.

Specific embodiments of non-degradable materials are: Polyetherketone(PEEK Optima, Grades 450 and 150, Invibio Ltd), Polyetherimide,Polyamide 12, Polyamide 11, Polyamide 6, Polyamide 66, Polycarbonate,Polymethylmethacrylate, Polyoxymethylene, or polycarbonateurethane (inparticular Bionate by DSM). An overview table of polymers andapplications is listed in Wintermantel, page 150; specific examples canbe found in Wintermantel page 161 ff. (PE, Hostalen Gur 812, Höchst AG),pages 164 ff. (PET) 169 ff. (PA, namely PA 6 and PA 66), 171 ff. (PTFE),173 ff. (PMMA), 180 (PUR, see table), 186 ff. (PEEK), 189 ff. (PSU), 191ff (POM-Polyacetal, tradenames Delrin, Tenac, has also been used inendoprostheses by Protec).

The material having thermoplastic properties may further contain foreignphases or compounds serving further functions. In particular, thethermoplastic material may be strengthened by admixed fibers or whiskers(e.g. of calcium phosphate ceramics or glasses) and such represent acomposite material. The material having thermoplastic properties mayfurther contain components which expand or dissolve (create pores) insitu (e.g. polyesters, polysaccharides, hydrogels, sodium phosphates),compounds which render the implant opaque and therewith visible forX-ray, or compounds to be released in situ and having a therapeuticeffect, e.g. promotion of healing and regeneration (e.g. growth factors,antibiotics, inflammation inhibitors or buffers such as sodium phosphateor calcium carbonate against adverse effects of acidic decomposition).If the thermoplastic material is resorbable, release of such compoundsis delayed. If the device is to be anchored not with the aid ofvibration energy but with the aid of electromagnetic radiation, theliquefiable material having thermoplastic properties may locally containcompounds (particulate or molecular) which are capable of absorbing suchradiation of a specific frequency range (in particular of the visible orinfrared frequency range), e.g. calcium phosphates, calcium carbonates,sodium phosphates, titanium oxide, mica, saturated fatty acids,polysaccharides, glucose or mixtures thereof.

Fillers used may include degradable, osseostimulative fillers to be usedin degradable polymers, including: β-Tricalciumphosphate (TCP),Hydroxyapatite (HA, <90% crystallinity); or mixtures of TCP, HA, DHCP,Bioglasses (see Wintermantel). Osseo-integration stimulating fillersthat are only partially or hardly degradable, for non degradablepolymers include: Bioglasses, Hydroxyapatite (>90% crystallinity),HAPEX®, see S M Rea et al., J Mater Sci Mater Med. 2004 September;15(9):997-1005; for hydroxyapatite see also L. Fang et al., Biomaterials2006 July; 27(20):3701-7, M. Huang et al., J Mater Sci Mater Med 2003July; 14(7):655-60, and W. Bonfield and E. Tanner, Materials World 1997January; 5 no. 1:18-20. Embodiments of bioactive fillers and theirdiscussion can for example be found in X. Huang and X. Miao, J BiomaterApp. 2007 April; 21(4):351-74), J A Juhasz et al. Biomaterials, 2004March; 25(6):949-55. Particulate filler types include: coarse type: 5-20μm (contents, preferentially 10-25% by volume), sub-micron (nanofillersas from precipitation, preferentially plate like aspect ratio >10, 10-50nm, contents 0.5 to 5% by volume).

Portions of the implantable device or device part which do not serve theanchoring and sealing function my consist of any suitablematerial/material combination (e.g. polymer, metal, ceramic, glass)which material may be bio-resorbable or not bio-resorbable andliquefiable or not liquefiable.

The devices and methods according to the invention are in particularsuitable for minimally invasive surgery but are also applicable in opensurgery.

Instead of for delivering material or signals to a human or animal body,it is possible also to use the device according to the aspect of theinvention for delivering energy to tissue, in particular in the form ofradiation (e.g. gamma-radiation, electromagnetic radiation such as e.g.infrared light).

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is described in further detail in connection with theappended Figs., wherein:

FIGS. 1 and 2 show an exemplary device according to embodiments of theinvention and an exemplary application (intra-osseous drug delivery)thereof, the devices serving for fixed implantation and being equippedfor e.g. drug delivery to the non-accessible side of a hard tissue layerthrough which the device is implanted;

FIGS. 3 and 4 show exemplary devices according to embodiments of theinvention and an exemplary application (intra-articular drug delivery)thereof, the devices serving for fixed implantation and being equippedfor e.g. drug delivery to the accessible side of a hard tissue layerthrough which the device is implanted;

FIGS. 5 and 6 show further embodiments of devices according toembodiments of the invention, the devices serving again for e.g. drugdelivery on the non-accessible side (FIG. 5) or the accessible side(FIG. 6) of a hard tissue layer;

FIGS. 7 to 13 show further exemplary embodiments of the device accordingto embodiments of the invention, the devices again being equipped fore.g. drug delivery to the non-accessible side of a hard tissue layerthrough which the device is implanted;

FIG. 14 shows a further exemplary embodiment of the device according toembodiments of the invention, the device again being equipped for e.g.drug delivery to the accessible side of a hard tissue layer throughwhich the device is implanted;

FIG. 15 shows a further exemplary embodiment of the device according toembodiments of the invention, the device again being equipped for e.g.drug delivery to the non-accessible side of a hard tissue layer throughwhich the device is implanted;

FIG. 16 shows an exemplary embodiment of a device part according toembodiments of the invention, the device part constituting an accessport reaching from the accessible side to the non-accessible side of ahard tissue layer (e.g. to inside of cranial bone or to medullary cavityof tubular bone).

FIGS. 17 and 18 show successive phases of exemplary methods forpercutaneous implantation of a device or device part according toembodiments of the invention;

FIGS. 19 to 21 show further exemplary applications of the methodaccording to the embodiments of invention

FIGS. 22 and 23 show further exemplary methods according to embodimentsof the invention near a soft and hard tissue or tissue replacementmaterial interface

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

FIG. 1 shows an exemplified embodiment of an implantable drug deliverydevice according to the invention. The device is suitable for drugdelivery D to tissue situated on a non-accessible side of a hard tissuelayer (i.e. side which is accessible only through the hard tissuelayer), in the exemplary case as illustrated drug delivery to cancellousbone tissue 1 beneath a cortical bone layer 2 (intra-osseous drugdelivery). For implantation of the device, the cortical bone layer 2 isperforated from its accessible side opposite the cancellous bone tissue.FIG. 1 shows the device, axially sectioned, ready for implantation (lefthand side) and after implantation (right hand side).

The device comprises a plug portion P and a container 3 which e.g.extends distally of the plug portion P and is substantially cylindrical.The container 3 has a distal wall portion 5 which is perforated,fenestrated, or otherwise suitably permeable (distal portion of lateralwall and/or distal wall of a cylindrical container) and a proximal wallportion 6 which is non-permeable (proximal wall and/or proximal part oflateral wall of a cylindrical container). In the illustrated case, thenon-permeable proximal wall portion is constituted by the plug portionP. The ring 7 of the material having thermoplastic properties isarranged between permeable and non-permeable wall portion, in theillustrated case around the plug portion P or the proximal region of thecylindrical container 3 respectively and preferably has a slightlylarger diameter than the lateral container wall. The container 3 is e.g.made of a metal, a ceramic material or of a polymer material which mayor may not have thermoplastic properties, in particular, it may be madeof the same material having thermoplastic properties as the ring 7. Anaxial length of the device is preferably greater than the thickness ofthe hard tissue layer (e.g. cortical bone layer 2) through which thedevice is to be implanted. The drug or a combination of drug and drugcarrier (e.g. drug integrated in drug carrier particles 8, in drugcarrier tablets or in a drug carrier gel) is contained within thecontainer 3.

For implanting the device of FIG. 1, an opening 9 is provided in thedesired location of the bone, wherein a proximal cross section of thedevice or of the ring 7 respectively is slightly larger than the crosssection of the mouth of the opening, and wherein the opening reachesinto the cancellous bone tissue 1 to a depth which is sufficient foraccommodating the container portion having permeable walls. The deviceis positioned in the opening 9 with the ring 7 sitting in the opening oron the mouth of the opening. Then energy is transferred at least to thering 7 and the device is at the same time pressed into the opening 9.For this purpose, e.g. a sonotrode 10 coupled to an active ultrasonicdevice is applied to the positioned device and pressed against thelatter, wherein the sonotrode e.g. has a cross section adapted to thering 7 as illustrated. The sonotrode 10 may also be equipped with meansfor holding the device and be used also for positioning the device forimplantation (not shown).

Vibration and pressing cause friction between the bone wall of the mouthregion of the opening 9 and the ring 7 to generate heat for liquefactionof the ring material, which at the same time is brought into intimatecontact with this bone wall. Simultaneously, the device is moved deeperinto the opening. The vibration is stopped advantageously when theproximal face of the device is about flush with the bone surface,although, on stopping the vibration, the proximal face of the device mayalso be situated above or below the bone surface as long as the achievedanchorage of the ring 7 in the cortical bone layer 2 and advantageouslyin a transition region between cortical and cancellous bone tissue issufficient to form a complete sealing ring 11.

As shown on the right hand side of FIG. 1, on re-solidification of thering material, this material forms a sealing connection (sealing ring11) with the bone tissue and, if this bone tissue comprisescorresponding cavities or pores, a positive fit connection with the bonetissue. For achieving such positive fit connection in hard tissue havingonly little natural porosity such as cortical bone, e.g. a thread orother suitable surface structure may be provided in the mouth region ofthe opening 9. A positive fit connection can be achieved also with aring 7 being dimensioned for reaching deep enough into the opening 9such that ring material is liquefied not only in the depth of thecortical bone layer but also in the depth of a transition zone betweencortical and cancellous bone, where the bone tissue comprises enoughporosity for achieving a positive fit connection.

In addition to extending on the distal side of the plug portion P, thecontainer may also extend through the plug portion and on the proximalside of the plug portion (similar to the device shown in FIG. 3), buthaving in the named regions no permeable walls, wherein afterimplantation the proximal container part will protrude from the corticalbone on its accessible side.

Instead of using vibrational energy for the implantation process asillustrated in FIG. 1 it is possible also to use a pressing toolcomprising a light guide connected to a laser light source and suitablefor transmitting laser light into or through the ring 7 to be absorbedin the ring or beneath the ring for providing the thermal energynecessary for liquefaction of the ring material. Alternatively, the ring7 or device portions adjacent to the ring may be equipped for resistiveor inductive heating and the pressing tool is equipped for transmittingthe necessary electric or electromagnetic energy.

As mentioned above, the drug (as an example of the material or signaldelivery or acquisition portion of the device) is arranged inside thecontainer 3. The configuration in which the drug is present and thecontainer perforation, fenestration, or other suitable permeability areadapted to each other to achieve a desired delivery rate and/or deliveryprofile. If the permeable distal wall portion is designed such that itconstitutes no substantial hindrance or a baffle only for the passage ofthe drug, a desired delivery rate and/or profile is to be achieved byproviding inside the container a suitable combination of drug and drugcarrier (further example of the material or signal delivery oracquisition portion of the device), i.e. a complete drug deliverysystem, for which the implantable container figures as means for fixedimplantation only and influences the characteristics of the deliveryprocess to a very small degree at the most. Such a drug delivery systemmay comprise one or a plurality of per se known drug carriers such as agel, liposomes, nanoparticles, microspheres, beads or tablets, in whichthe drug is integrated, or containments, capsules or porous bodies ofe.g. a polymer, ceramic or metallic material, in which the drug iscontained. The drug is released from the delivery system due tobioresorption, dissolution or disintegration of the carrier material ordue to diffusion or osmosis.

The above discussed permeability of container wall portions is to beadapted to the use of the device, which means that in a device formaterial delivery or acquisition such permeability is to enable passageof the application specific materials, in a device for signal deliveryor acquisition the permeability is to enable passage of the specificsignals.

On the other hand, it is possible also that the container 3 is equippedto play a more direct role in the drug delivery process. Its permeabledistal wall portion 5 may e.g. be made at least partly of abioresorbable, soluble or disintegrating material which becomespermeable for the drug only after a specified degree of resorption,dissolution or disintegration (delayed delivery). Furthermore, thepermeability of the wall 5 may be so restricted as to limit the drugdelivery rate as desired (slow delivery) without the necessity offurther limiting means such as the above named drug carriers.Furthermore, a fenestration of the permeable wall section may be closedby a semipermeable membrane through which an osmotic pump driving thedelivery system is fed.

FIG. 2 illustrates an exemplary application of the intra-osseous drugdelivery D with the aid of a device according to FIG. 1. The device asillustrated is implanted on a lateral side of the tibial condyle justbelow the capsule of the knee joint, the intra-osseous drug delivery D(illustrated as arrows and dark dots spreading in the bone tissue awayfrom the drug delivery device) being aimed at bone tissue near thearticular surface of the tibia.

Local intra-osseous drug delivery with the aid of a drug deliverydevice, as illustrated in FIG. 1 or 2, may e.g. serve for delivery intothe bone tissue of an antibiotic or anti-inflammatory drug, of a drugfurthering bone regeneration, or a drug for battling bone cancer.Exemplary applications are: local prophylaxis and supportive treatmentof chronic or acute osteomyelitis in a human patient (e.g. after openfracture or bone surgery) by local slow-release intra-osseous deliveryof an antibiotic formulation (e.g. gentamicin, vancomycin, amoxicillin,cephalosporine); prophylaxis or treatment of infections subsequent toendoprosthesis surgery (primary or redo surgery) by local slow-releaseintra-osseous delivery of an antibiotic (e.g. gentamicin or vancomycin)near the part of the endoprothesis which is embedded in bone tissue;therapy or prophylaxis of osteomyelitis, septic phycitis or bonefracture infection in animal patients by local slow-releaseintra-osseous delivery of an antibiotic (e.g. gentamicin, amikacin,cephalosporine); prophylactic and therapeutic treatment (acute orsecondary treatment) of complex and difficult to heal fractures,pseudoarthritis and non-union fractures by local intra-osseous deliveryof bone growth factor (e.g. BMP-2 or BMP-7) near the fracture site;support of spinal fusion by controlled local intra-osseous delivery of abone growth factor (e.g. BMP-2 or BMP-7) near or at the fusion site;support of tendon or ligament repair by local delivery of a bone growthfactor (e.g. BMP-2 or BMP-7) near the tendon/bone or ligament/boneinterface; palliative local treatment of inoperable symptomatic orunstable bone metastases or adjuvant therapy after surgical removal(e.g. grade IV breast and prostate cancer with one or more symptomaticbone metastasis) by slow-release intra-osseous delivery of an anticancerdrug (e.g. methotrexate or cisplatin) in or proximal to the metastaticlesion; bone regeneration after surgical removal of symptomatic orunstable bone metastases by slow-release intra-osseous delivery of adrug that stimulates bone formation and/or inhibits bone destruction(e.g. bone growth factors, bisphosphonates); treatment of avascular bonenecrosis; treatment against local pain.

In all above listed applications, the drug delivery device according tothe invention is preferably implanted through a cortical bone layer andequipped for delivery in the cancellous bone therewith restrictingdelivery to the bone tissue. However it is possible also to implant asimilar device through a surgically made bone surface without a corticallayer and therewith out a sealing function. Such implantation is e.g.possible in the applications of prophylaxis of infections subsequent toendoprosthesis surgery (primary or redo surgery) by local slow-releasedelivery of an antibiotic (e.g. gentamicin or vancomycin) near theendoprosthesis surface in contact with bone tissue.

Instead of for local drug delivery, the device and method according toFIGS. 1 and 2 are also suitable for systemic delivery, wherein the drugis delivered to the cancellous bone tissue and the excellent bloodsupply within this cancellous bone tissue is exploited. Instead ofintra-osseous drug delivery, device and method as illustrated in FIGS. 1and 2 may also be used for extra-osseous delivery on a non-accessibleside of a hard tissue (e.g. bone) layer, if the device is implantedthrough the hard tissue layer and reaching into a body cavity or intoother tissue on the non-accessible side of the hard tissue layer.Applications for such use are e.g. drug delivery through the skull boneinto the intracranial space or the cerebrospinal fluid respectively,delivery through a long bone into the medullary cavity or the bonemarrow respectively, or delivery through facial bone into a sinuscavity.

FIG. 3 illustrates a further embodiment of device and method accordingto the invention, which however has many similarities with theembodiment according to FIG. 1. Same items are denominated with samereference numerals as in FIG. 1. Other than the device according to FIG.1, the device according to FIG. 3 is designed for drug delivery D on theaccessible side of the hard tissue layer (cortical bone layer 2) throughwhich it is implanted (extra-osseous drug delivery on the accessibleside of a hard tissue layer, e.g. drug delivery into a cavity or tissueadjacent the cortical bone layer, e.g. into a joint capsule). For thisreason the distal wall portion 5 of the container 3 is non-permeable andthe proximal wall portion 6 is permeable and may or may not extendproximally from the plug portion P or the ring 7 of the thermoplasticmaterial, which as in FIG. 1 separates the two wall portions 5 and 6.This ring 7 is e.g. arranged in an undercut groove running around thedevice, wherein the ring protrudes from the groove such increasing thediameter of the container slightly (plug portion P). It is obvious thatsuch a ring does not need to be complete to start with, but may comprisecircumferential gaps as long as it comprises enough of the thermoplasticmaterial to, in the liquefied state, fill the whole groove andconstitute a sufficient sealing ring 11.

As shown on the right hand side of FIG. 3, the device is not implantedto be flush with the bone surface, but in the implanted state protrudesfrom the opening 9. Alternatively the device may be implanted to beflush with the bone surface, in which case, the ring 7 of thermoplasticmaterial would be positioned at the proximal device end (as illustratedin FIG. 1) and the permeable proximal wall portion 6 would be restrictedto the proximal device face. As discussed in connection with FIG. 1,also the device according to FIG. 3 may be made of at least twodifferent materials or it may consist fully of the material havingthermoplastic properties, wherein the ring 7 would be an integral partof the whole device and would preferably protrude slightly over thelateral container wall.

FIG. 4 shows in the same manner as FIG. 2 an exemplary application ofthe device according to FIG. 3, which is implanted on a lateral side ofa femoral condyle within the capsule of a knee joint, the drug deliveryD (illustrated with dark dots) being aimed at the synovial liquidcontained in the capsule or at tissue (e.g. cartilage) being in contactwith the synovial liquid. Exemplary applications of such drug deliveryconcern the local supportive treatment or prophylaxis of acute,sub-acute or chronic joint infections (e.g. septic arthritis with orwithout adjacent bone and soft tissue involvement) in an animal patientby slow-release intra-articular delivery of an antibiotic (e.g.gentamicin, amikacin, cephalosporin) into the synovial liquid of theaffected joint or long-term therapy of inflammatory or degenerativejoint diseases by long-term delivery of an anti-inflammatory drug (e.g.cortisone) into the synovial liquid of the affected joint. In the samemanner as above described for implantation inside a joint capsule, thedevice may be implanted in other bones, the drug delivery being aimed ata cavity or liquid or at a tissue other than bone tissue on theaccessible side of the bone.

FIG. 5 shows a drug delivery device (implanted configuration) which isvery similar to the drug delivery device according to FIG. 1. Other thanshown in FIG. 1 the ring 7 of the material having thermoplasticproperties is not arranged around a plug portion to be introduced intothe opening 9, but on the hard tissue facing surface of a cover portionC for the ring material to be anchored in the hard tissue surface aroundthe mouth of the opening 9. Therefore, the ring 7 has a diameter largerthan the diameter of the opening 9. The device comprises again acontainer 3 with a distal and a proximal wall portion (5, 6), whereinthe proximal wall portion 6 is constituted by the cover portion C and isnon-permeable and wherein the distal wall portion 5 comprises aperforation, fenestration or other suitable permeability and extendsdistally from the cover portion C. FIG. 5 shows the implanted device,the ring 7 being sealingly anchored in the outer surface of the corticalbone layer 2 and there constituting the sealing ring 11. For achieving agood seal and a positive fit connection between the bone tissue and thering 7 it may be advantageous to roughen the named bone surface beforeimplanting the device.

Of course it is possible to dimension and/or equip the container areaadjoining the cover portion C of the device of FIG. 5 as a plug portion,i.e. comprising a further ring of a material having thermoplasticproperties, and to anchor not only the ring of the cover portion C inthe bone surface but also the ring of the plug portion in the wall ofthe opening, wherein it is a condition that the anchorage of both ringstogether form a complete sealing ring 11, but wherein it is not acondition that each ring by itself forms a complete sealing ring.

FIG. 6 shows a further drug delivery device which is similar to the drugdelivery device according to FIG. 5 but, when implanted through a hardtissue (e.g. bone) layer, serves for (extra-osseous) drug delivery onthe accessible side of the hard tissue layer, as described above inconnection with FIGS. 3 and 4 (e.g. intra-articular drug delivery, i.e.drug delivery into the synovial fluid of a synovial joint).

The device according to FIG. 6 differs form the device according to FIG.5 in that it is the proximal wall portion 6 (cover portion C) which ispermeable, while the distal wall portion 5 is non-permeable.

If the cover portion of the device as shown in FIG. 6 is fully made ofthe material having thermoplastic properties it may also be fixed to thebone surface around the opening 9 in an orientation opposite to theillustrated one, i.e. with the container extending in a proximaldirection, i.e. away from the bone surface. If implanted in such anorientation, the same device is capable of intra-osseous drug delivery,if the depth of the opening 9 is at least as great as the thickness ofthe cortical bone layer.

In both devices as shown in FIGS. 5 and 6, the container may extend intothe cover portion C or protrude proximally from the cover portion.Material, functions and applications of the devices as shown in FIGS. 5and 6 are substantially the same as the ones described in connectionwith the devices shown in FIGS. 1 to 4.

The drug delivery devices and implantation methods as illustrated byFIGS. 1 to 6 may be varied without departing from the invention e.g. inthe following manner:

Instead of substantially cylindrical, the device may be e.g. conical orstepped and fit into a tapering or stepped hard tissue opening. Also theaxial length of the device may be larger, the same or smaller than itsdiameter and the device and/or the ring of the thermoplastic materialmay have a cross section of any form, in particular a non-circular crosssection. The great variability of the form of the device and therewithof the form of the container 3 allows adaptation to a large number ofdrug/carrier combinations which are available on the market foradministration other than with the aid of a device according to theinvention.

The container of the device may comprise a closable proximal openingwhich is suitable for the drug or drug/carrier combination to be filledinto the container, when the device or part thereof is positioned forimplantation or is implanted in the hard tissue already. The opening isthen closed by e.g. ultrasonically welding a closure element into it,which closure element may at the same time constitute the cover or plugportion of the device and is anchored in the hard tissue for producingthe sealing ring simultaneously with being welded to a lateral wallportion of the container for closing the container.

A proximal opening of the container may be capable of being closed,re-opened and re-closed (e.g. a septum to be penetrated with a hollowneedle). The drug or drug/carrier composition is filled into theimplanted device through the opening and the opening is then closed orcloses itself. For re-filling (in the implanted configuration of thedevice), the opening is re-opened and then re-closed.

A permeable distal or proximal wall portion of the container may beflexible (e.g. consisting of a textile material) and attached to a nonflexible plug or cover portion.

The device comprises instead of a container, a drug/carrier combinationwhich is capable of taking over the function of at least the permeabledistal or proximal wall portion and which is attached to the plug orcover portion of the device. Such drug/carrier combinations are e.g.pieces of a bioresorbable material or a material with an open porosity.

Instead of or in addition to a drug or drug/carrier combination, thecontainer may contain other material or signal delivery or acquisitionportions such as e.g. an electronic element and serve, possibly incooperation with further device parts, for signal delivery oracquisition within the body in which it is implanted. Depending on thesignals to be emitted or received and depending on the material of thecontainer walls it may in such a case not be necessary for the containerwalls to comprise perforations. The electronic element is e.g. anRFID-chip. It is possible also to attach the electronic or other signalemitting or receiving element directly to the plug or cover portionwithout the use of a container.

Instead of or in addition to a drug or drug/carrier combination, thecontainer may comprise a radiation source for alpha- or beta-radiation,wherein wall portions not to be permeable for the radiation contain e.g.barium sulfate or tantalum.

Instead or in addition to a drug of drug/carrier combination, thecontainer contains cells in a suitable suspension or matrix, which cellsare capable of forming a locally desired tissue (stem cells or furtherdifferentiated cells such as e.g. osteoblasts) or are engineered forproduction of proteins suitable for local therapeutic or otherwisebeneficiary purposes (e.g. growth factor or bone morphogenic factor).

The device is equipped for drug delivery on the non-accessible side ofthe hard tissue layer through which it is implanted, in particular forintra-osseous delivery and is not implanted in a hard tissue openingwhich is specifically made for the implantation and correspondinglyadapted to the device, but it is implanted in an opening in the hardtissue layer of an other origin (e.g. surgery, accidental fraction). Foradapting the device to the opening it is possible to choose acorresponding device or to implant a plurality of devices such that thesealing function of each device is achieved by a sealing ring whichsealingly contacts not only the hard tissue but also one or a pluralityof other similar devices. The same applies for devices being implantedin openings adjacent to an endoprosthesis serving a completely differentpurpose from the purpose of the inventive device.

The above listed exemplary variations of the devices and methods asillustrated in FIGS. 1 to 6 are at least partly applicable also for thedevices and methods as illustrated in the following Figs., wherein oneskilled in the art will easily find possible combinations and possiblynecessary adaptations.

FIGS. 7 to 9 show further exemplary forms of the device according to theinvention as shown in FIGS. 1 and 2, the devices being applicable fordrug delivery on the non-accessible side of the hard tissue layerthrough which they are implanted (e.g. intra-osseous drug delivery) andcomprise substantially cylindrical containers 3 extending distally froma plug portion P and comprising a permeable distal wall portion 5.

According to FIGS. 7 and 8, the device comprises a substantiallycylindrical container 3 with a fenestrated distal wall portion 5 and aplug portion P constituting the ring of the thermoplastic material andthe non-permeable proximal wall portion (not visible) of the container.The drug or combination of drug and drug carrier (not shown) ispositioned in the container 3 either from its distal or proximal endwherein an entry port at the proximal end is to be tightly closed with acorresponding closure element (not shown) and an entry port at thedistal end is to be sufficiently closed with suitable means (e.g. crosspin 12 of FIG. 3) for preventing the drug or drug delivery systemrespectively from departing from the container for at least as long asthe device is not implanted yet. For application in the human locomotorsystem, devices as shown in FIGS. 7 and 8 have a length of e.g. between20 and 30 mm, outer diameters of e.g. 3 to 10 mm, and inner diameters of1 to 8 mm. The ring 7 has an outer diameter which is e.g. 1 mm largerthan the outer diameter of the distal container region and an axiallength of at least in the order of 5 mm (for intra-osseous drug deliveryor implantation through a cortical bone layer respectively). Forapplications in smaller and/or thinner human bones (e.g. neurosurgicaland maxillofacial applications) and in small animals the devices arecorrespondingly smaller, for applications in larger animalscorrespondingly larger (equine applications: device length up to e.g.150 mm).

Plug portion P and container 3 are e.g. made as one piece and consist ofthe material having thermoplastic properties, e.g. of polylactide. Ifthe material is bioresorbable, as is the case for polylactide, itsresorbability is to be adapted to the drug delivery process such thatresorption at least in the region of the ring 7 or the sealing ring 11respectively does not start or does not relevantly impair the sealingfunction before delivery of the drug is substantially complete.

FIG. 9 is an exploded axial section of a further exemplary form of thedevice according to the invention as shown in FIG. 1. The devicecomprises a tube element 13 having a perforated, fenestrated orotherwise suitably permeable wall and constituting together with adistal closure element 15 the permeable distal wall portion 5 of acontainer. The device further comprises a proximal closure element 14,which consists of the material having thermoplastic properties, has aslightly larger cross section than the tube element 13, and constitutesthe plug or cover portion P or C with the ring 7 of the material havingthermoplastic properties and the non-permeable proximal wall portion 6.Advantageously, both closure elements consist of the material havingthermoplastic properties and the tube element 13 is e.g. a metal tube.The device as shown in FIG. 9 is advantageously assembled and loadedwith the drug or drug/carrier combination or other element for materialor signal delivery or acquisition and is then implanted as describedfurther above for the device of FIG. 1. Depending on the depth of theopening provided in the hard tissue for the device, on the mechanicalproperties of the hard tissue on the bottom of this opening, and on theform of the distal face of the device, anchorage in the hard tissue inthe region of the distal closure element is possible similar to theanchoring in the mouth region of the opening.

Instead of the tube element 13 comprising the fenestration perforationor other permeability, the tube element 13 may have a non-permeable walland the distal closure element 15 may be correspondingly permeable. If,of the two closure elements, one is permeable and the other one isnon-permeable and both closure element have substantially the same form,it is possible to use the same device for applications as described inconnection with FIG. 2 and in connection with FIG. 4, wherein thedevice, depending on the application, is implanted with the permeableclosure element either leading or trailing.

FIG. 10 shows a further exemplary embodiment of a drug delivery deviceaccording to the invention which device is equipped for delivering adrug to the non-accessible side of a hard tissue layer, e.g. tocancellous bone 1 beneath a cortical bone layer 2. The device comprisesa plug portion P and/or a cover portion C adapted in the above describedmanner to the opening 9 which is provided in the bone tissue. The plugand/or cover portion substantially constitute the non-permeable proximalwall portion and the ring 7 of the material having thermoplasticproperties as discussed in connection with FIGS. 1 to 9, wherein thefunction of the permeable distal wall portion is taken over by the wallsof the opening 9 in the tissue on the non-accessible side of thepenetrated hard tissue layer (in particular cancellous bone tissue 1 onthe non-accessible side of the cortical bone layer 2). The drug ordrug/carrier combination or other material to be delivered to thecancellous bone tissue (e.g. bioresorbable carrier particles 8 ortablets in which a drug is integrated, a saline solution in which e.g. agrowth factor is suspended or dissolved or a suspension or suitablematrix comprising cells capable of producing e.g. extracellular bonematrix material or factors furthering bone growth) is introduced in theopening 9, the plug portion P and/or cover portion C is then sealinglyanchored in the wall of the opening 9 and/or in the bone surface aroundthe mouth of the opening substantially as described in connection withthe drug delivery devices as illustrated in FIGS. 1 to 9.

FIG. 11 shows a drug delivery device having similar features as thedevice illustrated by FIG. 10. The device comprises a plug portion P andextending distally from the latter a container having only lateral wallswhich may be perforated, fenestrated or otherwise permeable or not theabsent distal wall constituting the only or an additional fenestration.The plug portion constitutes the non-permeable proximal wall portion ofthe container. The device is implanted e.g. to cover a bone defect,wherein anchorage in the walls of the opening may extend over the wholeaxial length of the device (for non-permeable lateral wall or betweenfenestrations). As the container 3 of the device according to FIG. 11has no distal wall, it is advantageous to introduce the drug ordrug/carrier combination after implantation, e.g. through a lateralchannel 20 which is drilled after implantation of the device and which,after filling the container 3, is closed with e.g. a bone plug 21 or aplug of a material having thermoplastic properties being “welded” intothe channel 20 using ultrasonic vibration energy.

FIGS. 12 and 13 show again drug delivery devices for drug delivery onthe non accessible side of a hard tissue layer, e.g. to cancellous bonetissue 1 beneath a cortical bone layer 2 or to bone marrow in a longbone, wherein the drug is released at a distal device end only. Thedevices comprise again a container 3, wherein the lateral container wallis not permeable and therefore the whole axial length of the device mayconstitute the plug portion P or in other words the axial length of thering 7 of the material having thermoplastic properties and of thesealing ring 11 may extend over substantially the whole axial length ofthe device.

In the embodiment according to FIG. 12, the inner space of the container3 has a diameter adapted to the diameter of biodegradable drug carrierbeads 8 or tablets being arranged in this space in a row or chain, whichis biased against a slightly narrower distal exit port e.g. by a spring30. As soon as the first carrier bead nearest to the exit port isresorbed sufficiently to be capable to pass the exit port, the nextsecond carrier bead which beforehand was shielded from the resorbingmedia by the first carrier bead is pushed to the exit port and subjectedto resorption.

In the embodiment according to FIG. 13 the drug is contained in theshaft 31 of a nail-shaped drug carrier 32. The head 33 of thenail-shaped drug carrier does not contain the drug and fits as a closureelement onto the tube shaped container 3 or plug portion P respectively.The drug nail 32 is introduced into the plug portion P before or afterimplantation of the latter and the head 33 is advantageously welded(e.g. with the aid of ultrasonic vibration energy) to the proximal faceof the plug portion P. It is possible also to dimension and equip thehead 33 as a plug portion and/or closure portion C to be anchored in thewall of opening 9 and/or in the hard tissue surface around the mouth ofopening 9. In such a case, the tube-shaped container 3 is positioned inthe hard tissue opening, the drug nail 32 being introduced in the latterbefore or after positioning of the container and then the head is weldedto the container and at the same time anchored in the hard tissue. Drugdelivery is effected by biodegradation or dissolution of the shaft ofthe carrier nail or by diffusion out of this shaft.

FIG. 14 shows a further drug delivery device according to the inventionwhich device is suitable for drug delivery to the accessible side of thehard tissue layer through which the device is implanted. The devicecomprises a perforated or fenestrated drug container 3 or drug/carriertablet and a non-permeable plug portion P (possibly combined with acover portion C), wherein the drug container is releaseably attached toa proximal side of the plug or cover portion, e.g. with the aid of asnap connection 35. When attached, the container is situated on or abovethe hard tissue surface of the accessible side of the hard tissue layer.The plug portion is preferably implanted in the hard tissue openingbefore the container is attached to it.

FIG. 15 illustrates a further embodiment of a drug delivery deviceaccording to the invention and a method for implanting the device. Thedevice is equipped for drug delivery on the non-accessible side of ahard tissue layer, e.g. for intra-osseous drug delivery through acortical bone layer. However, if adapted as described further above forother embodiments of the device according to the invention, the devicemay also serve for drug delivery on the accessible side of the hardtissue layer.

The device comprises in a similar way as the device according to FIG. 9,a substantially cylindrical container constituted by a tube element 13with perforated or fenestrated walls 5 and a proximal closure element 14which constitutes the plug portion P possibly combined with a coverportion C, i.e. comprises a ring 7 of a material having thermoplasticproperties around the plug portion P and possibly also on the hardtissue facing surface of the cover portion C. The tube element 13 has anopen proximal end and an open or closed distal end, wherein the proximalclosure element 14 fits into the proximal open end and the tubeperforation continues right to this proximal end. The device may furthercomprise a distal closure element 15, which comprises a material havingthermoplastic properties being the same or different from the materialof the proximal closure element 14. The closure element 15 is positionedat the bottom of the tube element 13. It serves for anchoring the devicein the bottom of a hard tissue opening 9 for which purpose the distalend of the tube element 13 needs to comprise a perforated or fenestratedwall. The distal closure element may further serve for closing thedistal end of the tube element 13 and/or for strengthening cancellousbone tissue in the area of the distal device end.

FIG. 15 shows three successive phases (a) to (c) of the implantation ofthe drug delivery device as described above. In phase (a), the tubeelement 13 is positioned in the hard tissue opening 9, which isdimensioned such that, at least in the region of its mouth, the tubeelement 13 is closely surrounded by the wall of the opening. The distalend of the tube element 13 may or may not rest on the bottom of theopening 9 (the tube element 13 may freely hang in the opening, if itcomprises a proximal flange supported on the hard tissue surface aroundthe mouth of the opening). If applicable, the distal closure element 15is positioned at the bottom of the tube element 13 and a primarysonotrode 10′ is introduced into the tube element 13 for effecting thedistal anchorage by pressing the distal closure element 15 against thebottom of the tube element 13 and transmitting vibration to it for atleast partly liquefying the thermoplastic material of this closureelement and pressing it through the perforations or fenestrations of thetube element to penetrate tissue surrounding the latter.

In phase (b) the distal anchorage is completed and the primary sonotrode10′ removed. The drug or drug delivery composition (e.g. drugcontainment 42) is introduced into the tube element 13. The proximalclosure element 14 is positioned on or into the proximal end of the tubeelement 13 and a secondary sonotrode 10″ is applied to it for effectingclosure of the tube element 13 and simultaneously for sealinglyanchoring the tube element 13 in the hard tissue wall of the opening 9by liquefying the material of the circumferential surface of the plugportion P (ring 7) and pressing it through perforations or fenestrationsof the tube element 13 to get in contact with the walls of the opening 9in the region of its mouth. If applicable, further material havingthermoplastic properties arranged on the cover portion C is alsoliquefied. The re-solidified material then constitutes the sealing ring11 between the device and the wall of opening 9 and possibly the hardtissue surface around the mouth of opening 9.

When effecting the distal and proximal anchorage of the device as shownin FIG. 12 care is to be taken, that enough of the perforation orfenestration of the tube element 13 is kept free of the material havingthermoplastic properties for enabling passage of the drug. Theseperforations or fenestrations or another suitable permeability of thecontainer wall may in a manner as discussed already further aboveconstitute a simple baffle for the drug passage, wherein the drugdelivery is substantially controlled by the drug delivery systemcontained in the container, or they may play a more direct role in thecontrol of the drug delivery.

The exemplary embodiment of a drug delivery device according to theinvention as illustrated in FIG. 15 may be varied in the followingmanner:

The tube element 13 comprises a proximal flange, which is perforated orfenestrated and the proximal cover element 14 comprises a cover portionC whose ring 7 of the material having thermoplastic properties isanchored in the hard tissue surface through the flange perforations.

Anchorage of the tube element 13 may regard the complete perforationthereof, the proximal cover portion 14 being permeable, wherein in sucha case the device serves for drug delivery to the accessible side of thehard tissue layer in which it is implanted.

FIG. 16 illustrates an implantable device part which serves as accessport to a not directly accessible side of a hard tissue layer. Suchaccess ports may e.g. serve for temporal or permanent access for aninfusion cannula, a catheter, a sensor, an electrode, a light guide etc.wherein through the improvement according to the invention the naturalsealing function of the hard tissue layer, which is impaired byimplanting the access port, is fully mended. The access port as shown inFIG. 16 is implanted in a cranial bone for providing temporal orrepeated access to the inside of the skull. In the same way access portsmay be implanted through a tubular bone to provide access to themedullar cavity of the bone, through a cortical bone layer to provideaccess to cancellous bone tissue or a cyst or tumor beneath the corticalbone layer, through a facial bone to provide access to a sinus cavity orthrough a hard tissue opening which is closed by the device itself ase.g. a pocket caused by periodontitis between a tooth and the jaw boneThe access port constitutes a part of a device for material or signaldelivery or acquisition on the non-accessible side of the hard tissuelayer.

FIG. 16 shows the access port before implantation (above) and in animplanted state (below). The access port comprises a plug portion Pand/or a cover portion (not shown) as described above for drug deliverydevices. The plug portion P comprises a circumferential ring 7 of thematerial having thermoplastic properties and a central septum element 50of a material having elastic properties such that it is capable of beingperforated with an element of small cross section (e.g. cannula, hollowneedle) and to sealingly close the perforation around this element andagain on removal of this element. Such materials which are e.g.elastomers on a silicone-basis, are well known from closures ofcontainers allowing multiple access for filling syringes.

The access port is implanted in a through opening 9 provided in e.g. acranial bone 51 with the aid e.g. of a sonotrode 10 and, in theimplanted state, adjoins and is anchored in the walls of this opening 9with a sealing ring 11 which guarantees together with the septum element50 prevention of undesired passage through the cranial bone, wherein inthe illustrated case prevention of passage of e.g. bacteria isparticularly important.

Instead of comprising the septum element 50, the access port maycomprise e.g. a cannula, a sensor, an electrode or other elementreaching through the access port, which element is permanently installedin the access port and is temporally or permanently connected,connectable or cooperating with further device parts.

Applications of access ports as described above are e.g. providingaccess to a drug container located on the non-accessible side of thehard tissue layer for refilling, or emergency access to bone marrowthrough a wall of a tubular bone for administration of drugs to apatient suffering of peripheral vasculature collapse or in need ofadministration of a drug which is too aggressive for intravascularadministration. The access port may be permanently connected to a drugreservoir or drug pump arranged e.g. subcutaneously on the accessibleside of the hard tissue layer in which the access port is implanted andbeing activated e.g. from outside the body or by the signal of a sensorwhich also passes through the access port. The access port may also beused for temporal passage of a light guide, possibly comprising a distaldiffuser element, in order to deliver radiation energy (e.g. infraredlight) to the inaccessible side of a hard tissue layer, e.g. forphotodynamic therapy.

Instead of comprising the central septum element, the device accordingto FIG. 16 may comprise a central portion of a non-penetrable materialor may consist completely of the material having thermoplasticproperties. Such a device, which is implanted in the same manner as theaccess port according to FIG. 16, is part of a device serving for onlyone material delivery or acquisition step, wherein an opening throughthe hard tissue layer is provided, wherein material is delivered orremoved from the accessible side of the hard tissue layer through theopening using a cannula or hollow needle and wherein the opening is thenclosed with the aid of the plug and/or cover portion which together withthe cannula or hollow needle constitutes the full device for materialdelivery or acquisition.

FIG. 17 further illustrates percutaneous implantation of a device ordevice part as above described, in particular such implantation of adrug delivery device as described in connection with FIG. 1, 2, 7 or 8or of an access port as e.g. described in connection with FIG. 16 andproviding e.g. for permanent percutaneous access to the implanteddevice. FIG. 17 shows five successive phases (a) to (e) of theimplantation process.

Phase (a) shows a hollow punching tool 60 being connected to anultrasonic device 61 being positioned through the skin 62 on theaccessible side of the hard tissue layer (e.g. cortical bone layer 2) inthe position in which the device is to be implanted. The punching tool60 carries in a proximal position a sleeve 64 of a smaller axial length.With the aid of the ultrasonic device 61 the tool 60 is forced throughthe skin 62 and through the hard tissue layer 2 to a desired depth andsuch that the sleeve 64 is positioned on the surface of the hard tissuelayer 2 or slightly dug into it. Punching processes in which a punchingtool 60 is driven by ultrasonic vibration energy are described in thepublication US 2008/269649 whose disclosure is enclosed herein byreference.

Phase (b) shows the opening 9 being provided through the hard tissuelayer 2, the sleeve 64 being positioned on the mouth of the opening andthe punching tool 60 being removed together with the bone plug 9′ fromwithin the opening 9.

Phase (c) shows the implantable device 65 being held at the distal endof a sonotrode 10 and being introduced through the sleeve 64. Phase (d)shows the device 65 anchored in the hard tissue layer through thesealing ring 11 and percutaneously accessible through the sleeve 64 orthe skin 62 respectively and phase (e) shows the sleeve 64 closed with asuitable cover 66.

FIG. 18 illustrates a further embodiment of percutaneous implantation ofa device 65 according to the invention, which device is a drug deliverydevice serving for drug delivery on the non accessible side of the hardtissue layer 2 through which the device 65 is implanted. Theimplantation is shown in four successive phases (a) to (d). The deviceis similar to the devices as shown in FIGS. 12 and 13 and comprises anaxial channel whose distal mouth is initially blocked by a piercingelement 70 which, by suitable means arranged in the channel, isprevented from being forced into the channel but not prevented frombeing forced out of the distal end of the channel. The substantiallycylindrical device portion is preferably made of the material havingthermoplastic properties, as illustrated, but may also comprise ametallic core. The piercing element 70 is e.g. a metallic element with asharp distal end.

Phase (a) shows the device 65 being positioned for implantation and asonotrode 10 applied to the proximal face of the device, wherein aK-wire 71 may be installed already to pass through the sonotrode 10 intothe channel of the device 65. The device is forced through the skin 62and through the hard tissue layer 2 (e.g. cortical bone layer) andsimultaneously sealingly anchored (sealing ring 11) in the wall of thehard tissue layer 2 and possibly in tissue (e.g. cancellous bone tissue1) located underneath the hard tissue layer by applying a pressing forceand ultrasonic vibration energy to the sonotrode 10.

Phase (b) shows the device 65 implanted, the sonotrode 10 removed andthe piercing element 70 being forced out of channel with the aid of theK-wire 71 which may be installed only after removal of the sonotrode.

Phase (c) shows the K-wire 71 removed and a cannula 72 introduced intothe proximal mouth of the device channel for introducing the drug ordrug/carrier combination into the channel. Phase (d) shows the cannula72 removed and the device channel being closed by applying a furthersonotrode 10′″ to the proximal face of the device, wherein the furthersonotrode has a distal face which is suitable for forcing liquefiedmaterial into the proximal mouth of the channel.

FIG. 19 shows a further exemplary application of the invention. Thisapplication regards prophylactic or therapeutic delivery of an e.g.antibiotic drug in a body region of e.g. osteosynthetic surgery, inparticular such delivery between a bone surface and an osteosynthesisplate. Such plates are usually fixed to e.g. a fractured bone by bonescrews, which are screwed into an opening provided in the bone or bypins comprising a thermoplastic material which are anchored in anopening provided in the bone through in situ liquefaction and bonetissue penetration followed by resolidification (caused e.g. byultrasonic vibration applied to the pin), wherein the screw or pin ispossibly secured to the plate simultaneously or with subsequentmeasures. The plate usually comprises a series of through openings,wherein the number of openings is usually larger than the necessarynumber of screws or pins, such that the surgeon can choose the mostadvantageous positions for the screws or pins. As shown in FIG. 19, atleast one of such surplus openings is used for implanting the deviceaccording to the invention, wherein delivery of the drug is aimed at thegap between the plate and the bone surface underneath the plate.

FIG. 19 shows a section of an osteosynthesis plate 80 (or other platesuch as e.g. an anterior cervical plate), which is e.g. made of aresorbable polymeric material, the plate being positioned against asurface of an e.g. fractured bone with the aid of a screw 81 or athermoplastic pin 82, wherein both screw and pin reach through the plate80 into at least the cortical bone 2 or further into the cancellous bone1 for keeping plate and bone in a fixed local relationship. For bothscrew 81 and pin 82 the plate 80 comprises a through opening 83 and acorresponding opening is provided in the bone, wherein the pin 82 isanchored preferably in cortical and cancellous bone tissue, its headpossibly being welded into the through opening 83 of the plate duringthe same application of vibrational energy. In a further through opening83 and a corresponding opening in the bone, a device 65 according to theinvention, e.g. a device similar to the device shown in FIG. 3, isimplanted, the device being anchored as described further above at leastin the cortical bone, but possibly also in the cancellous bone tissuewhere the thermoplastic material forms a sealing ring 11 on a plugportion which together sealingly close the opening in the bone. A headportion 84 of the device may further be welded into the through opening83 of the plate 80 in a similar mariner as above described for thethermoplastic pin 82.

The device 65 comprises a container 3 with a permeable proximal wallportion 6, having a suitable permeability proximally adjacent to thenamed anchorage 11 and e.g. reaching up to the head portion 84. Such animplanted device enables drug delivery to the space between the bonesurface and an underside of the plate 80, which drug delivery isrestricted to this space by the sealing ring 11 on the bone side and theweld between drug delivery device 65 and plate 80 on the other side.

If so desired, it is possible to design the proximal face of the deviceaccording to FIG. 19 as a permeable wall also, such that not only thegap between the plate and the bone surface, i.e. the plate surfacefacing the bone tissue, is treated with the drug to be delivered butalso the opposite plate surface.

FIG. 20 shows a further application of the invention, wherein a drug,e.g. an antibiotic drug (drug delivery D), is delivered from drugdelivery devices 65 according to the invention, which devices areimplanted in the vicinity of an implanted endoprosthesis 90, wherein theendoprosthesis is partly implanted in a bone and partly protrudes fromthe bone to be adjacent to other tissues or further parts ofendoprostheses. The devices are equipped for drug delivery on theaccessible side of the bone in which they are implanted e.g. in themanner as described in combination with FIGS. 3, 4 and 6 and theydeliver a drug along the surface of the prosthesis part protruding fromthe bone (e.g. prophylactic antibiotic treatment).

FIG. 21 shows a further application of the invention, wherein a closureelement (as briefly described above in the context of FIG. 16) is usedfor sealing a blood vessel 92 (arteriole or venule) extending along acanal 93 within the trabecular structure 94 of canncellous bone andwhich is cut e.g. during bone surgery. Cutting through bone tissue mayresult in cutting through blood vessels of the named type. This may leadto a haemorrhage which is not easily stopped as the cut end of the bloodvessel 92 is immediately retracted from the cut bone surface 95 into thebone tissue where it cannot be closed by being clamped or cauterized.However, as shown on the right hand side of FIG. 21, such haemorrhagecan easily be stopped with the aid of a closure element 96 consisting ofa thermoplastic, preferably resorbable material or carrying at least aring of such a material around its circumference. Such a cover elementis chosen to have a size and form adapted to the open end of the canal93 as closely as possible and which is introduced into this canal endwith the aid of e.g. a vibrating tool (e.g. sonotrode of an ultrasonicdevice, not shown) and at the same time is sealingly anchored in thecanal wall near the cut end of the canal such stopping the haemorrhage.If, as illustrated in FIG. 21, the closure element is introduced intothe canal 93 such that its proximal face is flush with the cut surface95 of the bone tissue, the closure element 96 does not constitute anyhindrance for further surgical steps at the cut bone surface 95.

FIG. 22 shows a further embodiment drug delivery device 113 suitable fordrug delivery to the accessible side of the hard tissue/hard tissuereplacement material 112 (e.g. bone or bone replacement tissue) intowhich it is implanted near or at a tissue interface 111/112 which is aninterface of adjacent hard tissue/hard tissue replacement material 111and soft tissue/soft tissue replacement material 112 interface such as atendon/bone or ligament/bone interface for local delivery of a drug 115promoting healing of the surrounding tissue e.g. after an injury orrupture of a ligament or tendon or during replacement surgery of anatural joint with a prosthesis. In other embodiments the drug deliverydevice implanted near or at such a tissue interface 111/112 is suitablefor intra-osseous drug delivery and in yet further embodiments drug isdelivered both into the bone tissue and at or near the tissue interface111/112.

The one or more drug component 115 to be delivered by the drug deliverydevice 113 in this and other preferred embodiments of the invention areselected in particular from drugs promoting healing, in particularpromoting growth, differentiation and/or regeneration and are alsoselected from antibiotic and anti-inflammatory drugs. Such drugscomprise both proteinaceous drugs like growth and differentiationfactors e.g. the Bone Morphogenic Protein family (BMP 2, 6, 7, 12, 13),Insulin Growth Factor (e.g. IGF 1), Platelet Derived Growth Factor(PDGF), Growth and Differentiation Factor (e.g. GDF 5) etc. and alsonon-proteinaceous drugs including small molecules (e.g. biphosphonates).

In further embodiments of the method according to the invention thehealing is promoted and/or palliative local treatment of a inflamed orinjured tissue interface 111/112 as e.g. (partially) torn ligaments orinflamed tendons e.g. in chronic tendonitis is achieved by theimplantation of drug delivery device 113 near the tendon/bone orligament/bone interface i.e. at the interface or in the vicinitythereof. In preferred embodiments the drug delivery device 113 isimplanted in minimally invasive procedures.

FIG. 22 additionally shows a suture anchor 114 which is used inpreferred embodiments of the method according to the first or secondaspect of the invention. Here a suture anchor 114 for attaching a sutureto hard tissue 112 is also implanted in the vicinity of the tissueinterface 111/112 such as a tendon/bone or ligament/bone interface forsuturing the tendon or ligament into the hard tissue e.g. bone or bonereplacement material. Shown in FIG. 22 is a preferred embodiment inwhich the drug delivery device is implanted into the hard tissue layerdirectly at the tissue interface 111/112, here underneath the layer ofsoft tissue. In further embodiments the drug delivery device isimplanted in the vicinity of the tissue interface 111/112 rather thandirectly at the tissue interface 111/112. For example, in situations oflimited space or where there is (residual) partial attachment of thesoft tissue or in cases where an inflamed tissue interface region istreated the implantation of the drug delivery device 113 in the vicinityof the tendon/bone or ligament/bone interface may be preferable over animplantation into hard tissue or hard tissue replacement materialdirectly at the tissue interface 111/112.

Such a method combining the implantation of two types of implants, i.e.one or more drug delivery device 113 and one or more suture anchor 114for attaching a suture to a hard tissue, is generally applicable insurgical procedures, where tendons and ligaments need to be adapted tohard tissue (e.g. bone or bone replacement tissue). For example themethod of combining these two types of implants is applicable for repairof a torn rotator cuff by implanting both a suture anchor 114 forattaching a suture which attaches a torn rotator cuff tendon to ahumeral bone and implanting a drug delivery device 113 into the humeralbone. Further applications include attaching a torn Achilles' tendon byimplanting a device for attaching a suture which attaches the plantaris,gastrocnemius (calf) and soleus muscles to the calcaneus (heel) bone andalso implanting a drug delivery device implanted into the heel bone.

FIG. 23 illustrates a preferred method including the per se knownknotless double row procedure for suturing a soft tissue to a hardtissue, using the example of reattaching a torn rotator cuff tendon 100to humeral bone tissue 101 (or a corresponding endoprosthesis) in foursuccessive phases (a), (b), (c) and (d). Phase (a) is before the repairoperation and shows the location 102 in which reattachment is necessary.It also shows a region A of the bone tissue at the location in whichreattachment is necessary and in which region A at the interface 111/112at least one drug delivery device is implanted prior to the attachmentsteps in phase b) through d). After attachment of the soft tissue at thelocation 102, the region A comprising the implanted drug delivery deviceis at least partly covered by the soft tissue. In other embodiments atleast one drug delivery device is implanted into the hard tissue prior,during or after any one of the phases a) through d), at a region B whichlies in the vicinity of the location 102 where the attachment isnecessary. Region B is different from region A in that it either liesoutside of the soft tissue/hard tissue interface or in that it overlapswith interface 111/112 only to the extent that the region B during thesurgical procedure is accessible without detaching connections betweenthe soft and hard tissues or tissue replacement materials at theinterface. In phase (b) two medial anchors 103 are anchored in the bonetissue, in locations to eventually be underneath the tendon 100, eachone of the medial anchors 103 attaching at least one suture 4 to thebone tissue in a slideable manner. In phase (c) the end sections of eachsuture attached to one of the medial anchors is passed through the torntendon 100 and by tensioning the sutures away from the tendon end (notshown), the latter is pulled over the medial anchors 103. In phase (d)two lateral anchors 104 are anchored in the bone tissue just beyond theedge of the tear, the row of lateral anchors 104 running about parallelto the row of medial anchors 103, the end sections of the sutures 106being tensioned and locked with the aid of the lateral anchors 104 in across-wise manner, such that the two suture end sections held by onemedial anchor 103 are locked by two different lateral anchors 104 suchforming crossed suture bridges 105 between the row of medial anchors 103and the row of lateral anchors 104.

One skilled in the art is capable without undue experimentation tocombine features described for specific embodiments of device and methodaccording to the invention in different ways and such creating furtherembodiments without departing from the scope of the invention.

EXAMPLES

Devices as illustrated in FIG. 7 and consisting of PLA were loaded withpolylactide particles in which a few milligrams of methylene blue as amodel drug of low molecular weight were integrated. The loaded deviceswere implanted as shown in FIG. 2, in tibial bone near the knee joint ofsheep for intra-osseous delivery of the methylene blue. The tibial boneof sheep sacrificed 5 and 10 days after implantation was opticallyanalyzed and the methylene blue was found in the cancellous bone aroundthe implanted devices but none of it was detected in the periosteum orin any tissue adjoining the implantation site on the accessible side ofthe tibia bone.

The same experiment was carried out using devices substantially asillustrated in FIG. 3 and implanted as illustrated in FIG. 4 in tibialbone within the capsule of the knee joint of sheep for intra-articulardelivery of the methylene blue. In the sacrificed sheep the articularcartilage of the knee joints was found to be blue, but no methylene bluewas found in the cortical or cancellous bone surrounding the implant.

The results of the above described experiments show that the implantfully prevents a drug of small molecular weight to penetrate through thetibial cortical bone of sheep where the implant reaches through thiscortical bone, i.e. drug delivery is fully restricted to either thenon-accessible side or the accessible side of the cortical bone layer.

Devices as shown in FIG. 7 consisting of polylactide were loaded withgranules of a bone substitute material containing a bone morphogenicprotein (BMP) for intra-osseous delivery of the protein. Devicescontaining granules of the bone substitute material alone, i.e. withoutbone morphogenic protein were implanted as control. Implantation wascarried out in subchondral tibial bone beneath the knee joint of sheep,wherein the depth of the opening provided for the implantation wasgreater than the axial length of the device such that after implantationof the device there was an empty space in the cancellous bone below theimplanted device. In the sacrificed sheep new bone growth filled thehollow spaces below the loaded devices already after four weeks buthardly any was found underneath the control devices. No new bone growthor ossification of periosteum was found in the vicinity of the bonesurface near the implantation site (accessible side of the cortical bonelayer). This experiment shows that the thermal load to which the deviceis subjected on implantation is so small that the BMP being a very heatsensitive protein does not loose its efficacy. It further shows that,the same as the model drug methylene blue, the BMP is prevented frommigrating from the one side of the cortical bone where it is deliveredto the other side.

1. A device suitable for being implanted in a human or animal body andbeing equipped for material or signal delivery or acquisition withinsaid body or an implantable device part of such a device, the device ordevice part further being suitable for fixation on or in hard tissue orcorresponding replacement material wherein the device or device partcomprises: at least one of a plug portion (P) to be inserted in anopening in the hard tissue or replacement material and a cover portion(C) to be positioned over a mouth of such an opening in the hard tissueor replacement material, the plug or cover portion comprising a completering of a material having thermoplastic properties and being liquefiablethrough application of energy to the ring or to device portions adjacentto the ring, said ring being situated around a cross section of the plugportion (P) or on a tissue facing surface of the cover portion (C), andwherein the device or device part is equipped for transmission of energyto the ring or to the device portions adjacent to the ring for thepurpose of liquefying at least part of the material having thermoplasticproperties and to bring the material into contact with the hard tissueto form on re-solidification a complete sealing ring around the opening.2. The device or device part according to claim 1, wherein the completering of the material having thermoplastic properties is constituted by aring part or a plurality of ring parts arranged in a ring-shaped grooveand being capable of flowing together in the groove when liquefied toform the complete ring on implantation.
 3. The device or device partaccording to claim 1, wherein the device is equipped for material orsignal delivery or acquisition on a non-accessible side of a hard tissuelayer, and comprises a material or signal delivery or acquisitionportion arranged on a distal side of the plug or cover portion (P, C) orcomprising a container with a perforated, fenestrated or otherwisepermeable wall portion on a distal side of the plug or cover portion (P,C) and a non-permeable wall portion on the proximal side of the plug orcover portion (P, C) or constituted by the plug or cover portion (P, C),wherein the material or signal delivery or acquisition portion isarranged or arrangeable in the container.
 4. The device or device partaccording to claim 1, wherein the device is equipped for material orsignal delivery or acquisition on an accessible side of a hard tissuelayer, and comprises a material or signal delivery or acquisitionportion arranged on the proximal side of the plug or cover portion (P,C) or comprising a container with a non-permeable wall section on adistal side of the plug or cover portion (P, C) and a fenestrated,perforated or otherwise permeable wall portion on a proximal side of theplug or cover portion (P, C) or constituted by the plug or cover portion(P, C), wherein the material or signal delivery or acquisition portionis arranged or arrangeable in the container.
 5. The device or devicepart according to claim 1, wherein the device is equipped for materialor signal delivery or acquisition on a non-accessible side of a hardtissue layer, and comprises a non-permeable plug or cover portion (P, C)and a material or signal delivery or acquisition portion being separatefrom the plug or cover portion (P, C) and fitting into the opening inthe hard tissue which is closable by the plug or cover portion (P, C).6. The device or device part according to claim 3, wherein the materialor signal delivery or acquisition portion comprises at least one of adrug, a drug/carrier composition, a per se known drug delivery system,viable cells in a suspension or matrix, a therapeutically orprophylactically or otherwise active agent, an electronic ormicromechanic device, an RFID-chip, or a particle radiation source. 7.The device or device part according to claim 1, wherein the device partbeing equipped as an access port for accessing a non-accessible side ofthe hard tissue layer from an accessible side thereof.
 8. The devicepart according to claim 7, and comprising a plug portion (P) with a ringof the material having thermoplastic properties and a septum elementarranged inside the ring.
 9. A method of fixating a device suitable forbeing implanted in a human or animal body and being equipped formaterial or signal delivery or acquisition within said body or animplantable device part of such a device on or in hard tissue orcorresponding replacement material in said body, the method comprisingthe steps of: providing the device or device part with at least one of aplug portion and a cover portion comprising a complete ring of amaterial having thermoplastic properties, said ring being situatedaround a cross section of the plug portion or in a tissue facing surfaceof the cover portion, providing an opening in the hard tissue orreplacement material, the opening comprising a mouth in a surface of thehard tissue or replacement material and a wall of the hard tissue orreplacement material and further comprising a cross section adapted tosaid ring of said plug or cover portion, positioning the device ordevice part relative to said opening such that the plug portion reachesinto the opening or the cover portion faces the surface of the hardtissue or replacement material around the mouth of the opening and saidring extends around said opening in the vicinity of at least one of saidwall and said surface, transmitting energy to said ring for a timesufficient to liquefy at least part of said material havingthermoplastic properties and making it to contact the hard tissue orreplacement material of at least one of said wall and said surface allaround said opening, and letting the liquefied material re-solidify toconstitute a complete sealing ring in sealing contact with at least oneof said wall and said surface all around said opening.
 10. A method offixating a device suitable for being implanted in a human or animal bodyand being equipped for material or signal delivery or acquisition withinsaid body or an implantable device part of such a device on or in hardtissue or corresponding replacement material in said body, the methodcomprising the steps of: providing the device or device part with atleast one of a plug portion and a cover portion comprising a ring-shapedgroove containing a ring part or a plurality of ring parts of a materialhaving thermoplastic properties, said ring-shaped groove being situatedaround a cross section of the plug portion or in a tissue facing surfaceof the cover portion, providing an opening in the hard tissue orreplacement material, the opening comprising a mouth in a surface of thehard tissue or replacement material and a wall of the hard tissue orreplacement material and further comprising a cross section adapted tosaid ring-shaped groove of said plug or cover portion, positioning thedevice or device part relative to said opening such that the plugportion reaches into the opening or the cover portion faces the surfaceof the hard tissue or replacement material around the mouth of theopening and said ring-shaped groove extends around said opening in thevicinity of at least one of said wall and said surface, transmittingenergy to said ring part or ring parts for a time sufficient to liquefyat least part of said material having thermoplastic properties andmaking it to flow along the ring-shaped groove to form a complete ringand to contact the hard tissue or replacement material of at least oneof said wall and said surface all around said opening, and letting theliquefied material re-solidify to constitute a complete sealing ring insealing contact with at least one of said wall and said surface allaround said opening.
 11. A method of fixating a device suitable forbeing implanted in a human or animal body and being equipped formaterial or signal delivery or acquisition within said body or animplantable device part of such a device on or in hard tissue orcorresponding replacement material in said body, the method comprisingthe steps of: providing the device or device part with at least one of aplug portion and a cover portion comprising a complete ring of amaterial having thermoplastic properties or a part or parts of such aring in a ring-shaped groove, said ring or ring-shaped groove beingsituated around a cross section of the plug portion or in a tissuefacing surface of the cover portion, implanting the device or devicepart in an opening in the hard tissue or replacement material, theopening comprising a mouth at least partly in a surface of the hardtissue or replacement material and a wall at least partly of the hardtissue or replacement material and further comprising a cross section atleast partly adapted to said ring or ring-shaped groove of said plug orcover portion, by carrying out the steps of: positioning the device ordevice part relative to said opening such that the plug portion reachesinto the opening or the cover portion faces the surface of the hardtissue or replacement material around the mouth of the opening and saidring or ring-shaped groove extends at least partly around said openingin the vicinity of at least one of said wall and said surface,transmitting energy to said ring for a time sufficient to liquefy atleast part of said material having thermoplastic properties and makingit, if applicable, to flow in the ring-shaped groove to form a completering and to contact the hard tissue or replacement material of part ofsaid wall and said surface of said opening and a further implanted orimplantable device, and letting the liquefied material re-solidify toconstitute at least part of a sealing ring in sealing contact with partof at least one of said wall and said surface and the further implantedor implantable device.
 12. The method according to claim 9, wherein theopening in the hard tissue reaches through a hard tissue layer from anaccessible side to a non accessible side thereof.
 13. The methodaccording to claim 9, wherein the step of transmitting energy comprisesapplying a sonotrode coupled to an active ultrasonic device to aproximal end of the device or device part and therewith transmittingultrasonic vibratory energy to the device or device part andsimultaneously pressing the device or device part deeper into theopening.
 14. The method according to claim 9, wherein the step oftransmitting energy comprises transmitting laser light or electricenergy to the device or device part.
 15. The method according to claim9, wherein the hard tissue is bone tissue.
 16. The method according toclaim 12, wherein the hard tissue layer is one of a cortical bone layer,a wall of a tubular bone, a cranial bone and a facial bone.
 17. Themethod according to claim 9, wherein the opening in the hard tissue isprovided by punching of the hard tissue layer with a punching tool or byforcing the device through the hard tissue layer without providing anopening beforehand.
 18. The method according to claim 17, wherein thestep of punching or forcing is carried out percutaneously.
 19. Themethod according to claim 18, wherein the step of punching or forcing iscarried out with the aid of vibrational energy, wherein in the step offorcing the device is simultaneously anchored in the hard tissue byliquefaction of the material having thermoplastic properties.
 20. Amethod for stopping a haemorrhage from a blood vessel extending througha canal in bone tissue, the blood vessel having an open end inside acanal mouth in a bone surface of a surgical origin, the methodcomprising the steps of: Providing a closure element adapted in size andform to the canal mouth and comprising a ring of a maternal havingthermoplastic properties around a circumference, Positioning the closureelement in or on the canal mouth, transmitting energy to said ring andpressing the closure element further into the canal mouth for a timesufficient to liquefy at least part of said material havingthermoplastic properties and making it to contact the bone tissue allaround said canal mouth, and letting the liquefied material re-solidifyto constitute a complete sealing ring in sealing contact with the bonetissue all around said canal mouth.
 21. The method of according to claim9, wherein the device is equipped for drug delivery, the methodcomprising the further step of providing a tendon or ligament repairsite, wherein the device is implanted for local delivery of a bonegrowth factor near the tendon/bone or ligament/bone interface.
 22. Asurgical method of fastening soft tissue and/or soft tissue replacementmaterial to hard tissue and/or hard tissue replacement material, themethod comprising: fastening the soft tissue/soft tissue replacementmaterial to the hard tissue/hard tissue replacement material using atleast one fastener, implanting a device comprising surface regions of amaterial having thermoplastic properties and being liquefiable throughapplication of energy to the device, wherein the device is equipped forcausing at least part of the material having thermoplastic properties toliquefy and to bring the material into contact with the hard tissue/hardtissue replacement material to form on re-solidification an anchoring inthe hard tissue/hard tissue replacement material, the device furthercomprising a drug promoting healing, wherein the device is implanted atthe interface between the soft tissue/soft tissue replacement materialand the hard tissue/hard tissue replacement material or in a vicinitythereof.
 23. The method according to claim 22, wherein the drug forpromoting healing comprises at least one of: a growth factor, adifferentiation factor, a regeneration factor, an antibiotic, and ananti-inflammatory drug.
 24. The method according to claim 22, whereinthe at least one fastener comprises a suture, and wherein the step offastening the soft tissue/soft tissue replacement material to the hardtissue/hard tissue replacement material comprises the sub-steps ofproviding a suture anchor that comprises material liquefiable by theimpact of energy, of implanting the suture anchor by liquefying at leasta portion of the material and pressing a liquefied portion of thematerial into the hard tissue/replacement material, and of securing thesuture to the suture anchor.
 25. The method according to claim 22,wherein the at least one fastener comprises material liquefiable by theimpact of energy and is implanted by liquefying at least a portion ofthe material, pressing a liquefied portion of the material into the hardtissue/replacement material and letting the liquefied portionre-solidify to provide an anchoring.